Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10072034-B2
Application number	US-201715480689-A
Country	US
Kind code	B2
Filing date	Apr 6, 2017
Priority date	Apr 6, 2016
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

There are provided compounds of formula I,

wherein T, A, Q, Z, G, R 4 , R 5a , R 5b and n have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

First claim

The invention claimed is:

1. A compound of formula I,

wherein:
T represents:

W represents O, S or NCH 3 ;
V represents N or CR 1 ;
R 1 represents C 1-3 alkoxy, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, which latter four groups are optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy and C 1-2 alkoxy, or R 1 represents H;
R 2 represents —NR A1 S(O) 2 R B1 , —S(O) 1-2 R B2 , —P(O)R B3 R B4 , C(O)NR A2 R A3 or —CH 2 NR A4 C(O)R A5 ;
R A1 to R A5 independently represent H or C 1-3 alkyl optionally substituted by one or more substituents selected from the group consisting of halo, hydroxy, NR C R D and C 1-2 alkoxy, or R A2 and R A3 together represent C 3-6 n-alkylene or C 4-5 n-alkylene interrupted between C2 and C3 by —O—, —S(O) q — or —N(R E )—;
R B1 to R B4 independently represent C 1-3 alkyl or C 3-6 cycloalkyl, which latter two groups are optionally substituted by one or more halo substituents;
R C and R D independently represent H or C 1-3 alkyl, which latter substituent is optionally substituted by hydroxyl or C 1-2 alkoxy, or R C and R D together combine to form C 4-6 alkylene optionally interrupted between C2 and C3 by —O—, —S(O) q — or —N(R E )—;
R E represents H or methyl;
q represents 0, 1 or 2;
R 3 represents C 2-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl or C 3-7 cycloalkyl, which latter four groups are optionally substituted by hydroxyl, C 1-2 alkoxy or halo, or R 3 represents morpholinyl or trimethylsilyl;
A represents CH or N;
R 4 represents C 1-3 alkoxy, C 3-5 cycloalkoxy, or C 1-3 alkyl, which latter three groups are optionally substituted by one or more halo substituents, or R 4 represents ethynyl, cyano, S(O) 2 CH 3 , halo or H;
Q represents O, S(O) p , SO 2 N(R 6 ) or C(O)N(R 6 );
n represents 1, 2 or 3;
p represents 0, 1 or 2;
R 5a and R 5b independently represent H, methyl or halo, or R 5a and R 5b together represent C 2-6 n-alkylene;
when n represents 1, Z represents O, S or NR 7 or,
when n represents 2 or 3, Z represents either
an O-atom on each occurrence, or
either an S-atom or NR 7 on one occurrence and an O-atom on each other occurence;

R 6 and R 7 independently represent H or methyl;
G represents —[(CH 2 ) r -Het 1 ] 0-1 -C(O) 2 H or a carboxylic acid isostere;
r represents 0 or, when Het 1 is attached to (CH 2 ) r via a ring heteroatom, r may alternatively represent 1; and
Het 1 represents
a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from the group consisting of N, O and S or
a 4- to 7-membered heterocyclic group that is fully saturated or partially unsaturated, and is monocyclic or is fused or bridged bicyclic, which group contains one or more heteroatoms selected from the group consisting of N, O and S,

wherein Het 1 is optionally substituted by one or more substituents selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, halo, hydroxyl and oxo,
or a pharmaceutically acceptable salt thereof.

2. A compound of formula Iy,

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 that is 2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic acid.

4. A compound as claimed in claim 1 that is a compound of formula Ix or Ia,

wherein R 1 to R 4 , R 5a , R 5b , A, Q and n are defined in claim 1 , or a pharmaceutically acceptable salt thereof.

5. A compound as claimed in claim 1 that is a compound of formula Ib,

wherein R 2 , A, Q and n are defined in claim 1 , or a pharmaceutically acceptable salt thereof.

6. A compound as claimed in claim 1 , wherein:
R 1 represents methoxy or deuterated methoxy;
R 3 represents trimethylsilyl or —C(CH 3 ) 2 -R, wherein R represents ethynyl or methyl; and/or
R 4 represents cyclopropoxy or methoxy, which latter group is optionally substituted by one or more halo substituents.

7. A compound as claimed in claim 1 , wherein R 2 represents —C(O)NH 2 , —C(O)NHCH 3 , —S(O) 1-2 CH 3 , —S(O) 1-2 CH 2 CH 3 , —P(O)(CH 3 ) 2 , —N(CH 3 )S(O) 2 CH 3 , —NHS(O) 2 CH 2 CH 3 or —NHS(O) 2 CH 3 .

8. A compound as claimed in claim 1 , wherein A represents CH.

9. A compound as claimed in claim 1 , wherein Q represents C(O)NH, S(O), S(O) 2 or O.

10. A compound as claimed in claim 1 , wherein:
n represents 2;
R 5a and R 5b independently represent H or methyl or R 5a and R 5b together represent —(CH 2 ) 2 —; and/or
G represents —CO 2 H or -Het 1 -CO 2 H, wherein the -Het 1 -CO 2 H moiety is a structural fragment selected from the group consisting of:

or G represents a carboxylic acid isostere selected from the group consisting of tetrazolyl, —C(O)N(H)—S(O) 2 CH 3 , —C(O)N(H)—S(O) 2 N(CH 3 ) 2 ,

or a tautomer of any of the latter three groups.

11. A compound as claimed in claim 1 , wherein:
R 2 represents —NHS(O) 2 CH 3 ;
Q represents C(O)NH or O; and
n represents 2.

12. A compound as claimed in claim 1 which is a compound selected from the group consisting of:
2-(2-(2-(3-((4-((4-(3-(5-(tert-butyI)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)acetic acid;
2-(2-(2-(3-((4-((4-(3-(5-(tert-butyI)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)acetic acid;
2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)acetic acid;
2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfinyl)ethoxy)ethoxy)acetic acid;
2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)acetic acid;
2-(2-(2-((3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfinyl)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenyl)sulfonyl)ethoxy)ethoxy)acetic acid;
2-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-(trifluoromethyl)phenoxy)ethoxy)ethoxy)acetic acid;
6-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)pyridazine-3-carboxylic acid;
5-((2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxyphenoxy)ethoxy)methyl)-1,2,4-oxadia

Assignees

• Respivert Ltd
• Topivert Pharma Ltd

Inventors

• Fyfe Matthew Colin Thor
• Thom Stephen Malcolm

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P27/14

  Decongestants or antiallergics · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title